The Program Project Grant (PPG), "Cellular Decisions of Differentiation in the Gl Tract" integrates the efforts of three investigators (one basic science and two clinical) from three Departments at the University of Michigan Medical School. The central goals of the proposed studies are: (a) To understand how gastric epithelial cells develop and maintain their identity by expressing or responding to the peptide morphogen sonic hedgehog (Shh) (b) To investigate how the patterns of cellular differentiation in the acid-secreting epithelium of the stomach changes in response to pathological insults, e.g., inflammation (such insults can alter the identity of the gastric epithelium, such that it acquires a small intestinal phenotype). Subproject 1 entitled "Biology of a Sub-population of Gastric Progenitor Cells" will examine the time course of gastric progenitor (stem) cell development in the embryo and their response to Shh or the proinflammatory cytokine interferon gamma. Subproject #2 entitled, "Hedgehog signaling in stomach homeostasis and pathology," will use LacZ reporter mice to identify and characterize the gastric cell populations that express and respond to hedgehog signals. In addition, how hedgehog signals mediate the epithelial-mesenchymal crosstalk will be analyzed. Subproject #3 entitled "Role of Parietal Cell Hedgehog is normal and Inflamed Stomach," will focus on how biologically active Shh is generated from the parietal cell and mediates corpus-antral crosstalk. All projects focus on dissecting developmental pathways in the stomach and make extensive use of mouse models to interrogate important signaling pathways primarily related to Shh. Two Cores will assist the PPG investigators-the Cell Biology (Core A) and the Administrative (Core B). The Cell Biology Core will facilitate the analysis of the mouse models using state-of-the-art imaging and bioinformatics techniques. The Administrative Core will enhance the already strong interaction between these three investigators across department lines by organizing monthly joint meetings and co-sponsoring invited speakers. This will further our understanding of how gastric cells make decisions of identity and differentiation and provide clues on how their phenotype is altered by inflammatory signals as relevant to public health.